The objective of this study was to assess the efficacy of ketoprofen compared with ceftiofur hydrochloride for the treatment of acute puerperal metritis (APM). Specifically, we set out to compare the incidence of extended treatment (extT) between treatment groups, to determine the prevalence of purulent vaginal discharge (PVD) and milk yield on the first 3 milk tests postpartum, and to analyze reproductive performance of cows treated with ketoprofen or ceftiofur. Cows with rectal temperature ≥39.5°C and reddish-brown fetid vaginal discharge within the first 10 d in milk (DIM) were diagnosed with APM. Day of enrollment and first day of treatment was considered study day 1. Rectal temperature was recorded daily until study day 7. A total of 610 dairy cows with APM were enrolled in this randomized clinical trial. Cows meeting the inclusion criteria were allocated to treatment with ketoprofen (3 mg/kg of body weight, n = 300) or treatment with ceftiofur (1 mg/kg of body weight, n = 310) on study days 1, 2, and 3. Cows that showed rectal temperature ≥39.5°C between study days 4 and 7 received an extT with ceftiofur for 3 (ketoprofen group) or 2 (ceftiofur group) more days. Cows were examined with the Metricheck device (Simcro, Hamilton, New Zealand) between DIM 21 and 40, and vaginal discharge was categorized on a 5-point scale according to the presence of pus. Cows with a score ≥2 were classified as having PVD. Fifty-two cows (35 from ketoprofen group, 17 from ceftiofur group) were excluded from analysis due to missing protocol compliance (n = 37) or concurrent disease (n = 15). Cows treated with ketoprofen were more likely to have an extT than cows treated with ceftiofur (61 vs. 32%). Prevalence of PVD did not differ between the 2 treatment groups (ketoprofen, 56%; ceftiofur, 53%). Cows, however, that needed an extT after the initial 3-d treatment were more likely to develop PVD than cows without extT (64 vs. 46%). Treatment group did not affect milk yield (ketoprofen group, 35.5 ± 0.4 kg; ceftiofur group, 35.2 ± 0.3 kg), first artificial insemination pregnancy risk (ketoprofen group, 20% vs. ceftiofur group, 25%), median days to first artificial insemination [ketoprofen group, 73 d, 95% confidence interval (CI): 70-75 d vs. ceftiofur group, 75 d, 95% CI: 72-76 d] and median days to pregnancy (ketoprofen group, 144 d, 95% CI: 132-158 d vs. ceftiofur group, 133 d, 95% CI: 119-153 d). These results indicate that although cows initially treated with ketoprofen were more likely to receive extT, fewer doses of ceftiofur (1.83) were required compared with cows initially treated with ceftiofur (3.63). Moreover, the prevalence of PVD was not increased and milk yield and reproductive performance were not negatively affected by the initial treatment with ketoprofen.